Cardiovascular disease (CVD) is the number one cause of death in the United States and an important public health problem. Seasonal variation in CVD morbidity, with up to a 50% higher winter occurrence, has been observed for 80 years, yet the physiological parameters that precipitate this seasonal peak have not been defined. Preliminary data in healthy men suggest that hematocrit (Hct, a determinant of blood viscosity) peaks while plasma nitrite/nitrate (NOx, a stable metabolite of the vasodilator molecule, nitric oxide) troughs in late fall/early winter. Additionally, an imbalance between NOx and endothelin-1 (ET-1, a potent vasoconstrictor) may lead to a thrombotic event;yet, Hct, plasma NOx and plasma ET-1 have not been examined rigorously for potential links to the known seasonal variation in CVD events. The overall purpose of this R-21 proposal is to establish, first, in healthy adults, baseline data and temporal patterns for Hct, NOx, ET-1 and microvascular reactivity (ability of the microcirculation to respond to increased flow following occlusion). The specific aims are to examine: 1) Hct, NOx, and ET-1 at one month intervals for one year, 2) microvascular reactivity at one month intervals for one year, and 3) the impact of seasonal variation of Hct, NOx, and ET-1 on microvascular reactivity. This study will employ a 3 group, prospective, longitudinal design with repeated measures of Hct, NOx, ET-1, and microvascular reactivity. Dietary intake and physical activity will be controlled statistically. A convenience sample of 17 healthy young men (20-30 yrs old), 17 healthy middle-aged men (50-60 yrs old) and 17 healthy middle-aged post-menopausal women (50-60 yrs old) will be recruited. Plasma NOx and ET-1 will be measured using ELISA. Microvascular reactivity will be measured using laser Doppler fluxmetry before and after 3 min of brachial artery occlusion. A physical activity questionnaire (PASE) and a 7-day diet record will be used to measure the covariates. Hct, NOx, ET-1, and microvascular reactivity will be examined for seasonal variation, differences by age, differences by gender and relationships between the variables. This study, which is a new research direction for our multidisciplinary team, will assist us to bridge basic and applied science in one area of cardiovascular physiology. An understanding of the seasonal rhythms of these important cardiovascular parameters will lay the foundation for the development of future innovative pharmacologic and/or lifestyle interventions tailored to seasonal physiology and designed to decrease the incidence of CVD. PUBLIC HEALTH RELEVANCE: Cardiovascular morbidity and mortality are higher in the winter than the summer, but current interventions do not specifically target the prevention of cardiovascular events during the winter. Hematocrit, plasma nitrite/nitrate (NOx) and/or plasma endothelin-1 (ET-1) are important cardiovascular substances that impact microvascular reactivity. If it were known that hematocrit, plasma NOx and/or plasma ET-1 were related to altered microvascular reactivity during the winter, then, that would be the first step toward developing a novel and innovative approach to prevention and/or treatment of cardiovascular disease that would tailored to the seasonal physiology of middle-aged and older adults, the group at greatest risk for a cardiovascular disease event.